Xerostomia is a frequent side effect of external beam radiation therapy (XRT) for head and neck cancer and is not amenable to palliative therapies. This medical and quality of life issue thus remains an unmet healthcare need for the increasing number of individuals who will receive XRT treatment for this disease of increasing incidence. A recent approach for this disorder is based upon gene therapy restoration of salivary gland function. In this strategy, a recombinant adenoviral vector (Ad) is employed to deliver the aquaporin gene to epithelial cells of the salivary glands via direct intra-ductal instillation. Preliminary phase I human clinical trials at the NIH/National Institute of Dental Research have clearly shown that this approach can restore salivary flow with an amelioration of xerostomia symptoms. Based on these promising findings, it is logical to hypothesize that vector design advancements to improve further aquaporin gene delivery could enhance functional restoration of the salivary gland. In addition, the achievement of long term expression of the aquaporin gene would extend the symptomatic benefits of this gene therapy approach for xerostomia. Herein we will seek to address these vector aspects of xerostomia gene therapy to enable its full patient benefit value to be realized as a translational therapeutic. In the first regard, we hve developed tropism modified Ad which embody dramatically enhanced target cell infectivity. We hypothesize that these infectivity enhanced Ad can accomplish improved aquaporin gene transfer for ductal epithelial cells of the salivary gland thereby augmenting functional restoratio. In addition, we have developed high capacity gutless adenoviral vectors (HCAd) that allow long term gene expression. We hypothesize that this vector capacity will allow us to maintain long term aquaporin expression levels to allow for sustained functional reconstitution of the salivary gland. The studies we propose herein will establish the full rationale for the ultimate development of a novel gene therapy approach for XRT-induced xerostomia based on aquaporin delivery to the ductal epithelium of the salivary gland. We also note that our approach is clearly generalizable for the diverse pathobiologies etiologic of xerostermia (Sjorgen's syndrome, chronic sialadentitis, etc.). Data acquired herein thru this R21 Pilot Award can thus be leveraged for the acquisition of NCI translational mechanisms (NExT, etc.) to fully realize our bench-to-bed translational goals.